Molecular modeling of the complex of endothelin-1(ET-1) with the endothelin type A (ETA) receptor and the rational design of a peptide antagonist

ET-1 is the most potent vasoconstrictor known to date, causing vasoconstric tion when bound to the ETA receptor. Inhibitors of the binding of ET-I to t he ETA receptor would be of immense value as potential therapeutic agents i n the treatment of cardiovascular disorders such as angina and hypertension . We present here the rational design of such an inhibitor, which is arrive d at on the basis of a model of theET-1/ ETA receptor complex proposed by u s. The model is found to be consistent with binding and mutagenesis studies of ET-I as well as of BQ123, a known, potent ETA-selective antagonist whic h competes with ET-1 for receptor binding. BQ123 is a peptidic antagonist w hich is constrained to adopt a definite conformation on account of its cycl ic nature, The noncyclic peptide antagonist designed by us also has a uniqu e conformation because it contains two dehydro-Alanine (Delta Ala) residues which, on account of their planarity, cause the peptide backbone to bend i n a specific and predictable manner. The folding rules for peptides contain ing Delta Ala were derived in our earlier studies. Energy minimization and modelling of the complex of the designed peptide with the ETA receptor indi cate that the antagonist is ETA-selective and the binding is more stable an d more specific as compared to that of BQ123.